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US3775417A - Selective hydrogenation of tri-and tetrazoloisoquinolines - Google Patents

Selective hydrogenation of tri-and tetrazoloisoquinolines Download PDF

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US3775417A
US3775417A US00169521A US3775417DA US3775417A US 3775417 A US3775417 A US 3775417A US 00169521 A US00169521 A US 00169521A US 3775417D A US3775417D A US 3775417DA US 3775417 A US3775417 A US 3775417A
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isoquinoline
triazolo
reaction
chloro
catalyst
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Ruiter E De
H Reimlinger
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Mallinckrodt Chemical Works
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • the invention relates to a process for selectively hydrogenating triand tetrazoloisoquinolines in the 5,6 position. More particularly, the process comprises contacting a trior tetrazoloisoquinoline with hydrogen in the presence of a nickel, palladium, or platinum catalyst under carefully controlled conditions, which is described herein below.
  • R R RVRS, R and R individuallycan represent substitutents such "ice amino, aminoalkylam-ino, dialkylaminoalkylamino, dialkylaminoalkoxy, hydroxy, sulfhydryl, alkylthio, cyano, haloalkyl, aminoalkyl, and the like
  • Preferred R through R variables include hydrogen, bromo, chloro, lower alkoxy and lower alkyl (i.e., C -C alkyl and alkoxy) especially methoxy, methyl, and ethyl, lower alkylthio especially methylthio, cyano, amino, dimethylarnino, diethylamino, Z-aminoethylamino, 3-aminopropylamino, 2- dimethylaminoethylamino, 3-dimethylaminopropylaming, 2-dimethylaminoethoxy, aminoethyl, and the
  • R through R substituent group will contain not more than 20 carbon atoms, and preferably not more than 8 carbon atoms.
  • the R variable can represent alkyl, alkaryl, aralkyl, aryl, amino, haloalkyl, cycloalkyl, heterocyclic groups (particularly 5- or 6-membered rings containing oxygen or nitrogen as the hetero atom), and alkoxyalkyl.
  • R will contain not more than 20, and preferably not more than 10, carbon atoms.
  • Preferred R variables are lower alkyl (i.e., C -C alkyl) and especially methyl, trifiuoromethyl, and phenyl.
  • the R variable can be hydrogen, amino, or aliphatic, aromatic, cycloaliphatic, or heterocyclic groups containing up to 24 carbon atoms.
  • the hydrogenated products are compounds that can be represented by the formulas:
  • the s-triazolo[3,4,a]isoquinolines can be produced by reacting a l-hydrazinoisoquinoline with an acidic reagent such as an acyl halide, a carboxylic acid anhydride, an orthoformic ester, a carboxylic acid, carbon disulfide, cyanogen bromide, an isocyanate, or a urethane.
  • an acidic reagent such as an acyl halide, a carboxylic acid anhydride, an orthoformic ester, a carboxylic acid, carbon disulfide, cyanogen bromide, an isocyanate, or a urethane.
  • Illustrative s-triazolo[3,4-a]isoquinolines that can be used in the invention include, among others,
  • the s-triazolo[5,l-a]isoquinolines can be produced by the following sequence of reactions, starting with known types of reactants:
  • Reaction (a) is carried out by reacting a l-aminoisoquinoline with a nitrile.
  • a Lewis acid catalyst is used, although in some cases, no catalyst is needed.
  • the nitriles that are used are compounds of the formula:
  • R represents alkyl, alkaryl, aralkyl, aryl, haloalkyl, cycloalkyl, heterocyclic groups, alkoxyalkyl groups, and the like.
  • nitriles that can be used in the invention include the following compounds:
  • alkanenitriles having up to 20 carbon atoms.
  • the preferred alkanenitriles are those having up to six carbon atoms, and those having from two to four carbon atoms are more preferred.
  • nitriles include the aromatic and cycloalkyl nitriles such as the following compounds:
  • haloalkyl nitriles such as the following compounds:
  • chloroacetonitrile trichloroacetonitrile, trifluoroacetonitrile, fiuoroacetonitrile, B-chloropropionitrile, B-bromopropionitrile, 'y-chlorobutyronitrile, a-chloroisobutyronitrile,
  • Still other useful nitriles include the heterocyclic nitriles such as the following compounds:
  • nitriles that are employed in the invention are a well known class of compounds that can be obtained by known procedures.
  • Nitriles are readily prepared, for instance, by reaction of benzyl chlorides or primary or secondary alkyl chlorides with alkali metal cyanide, by reaction of potassium arylsulfonic acid salts with potassium cyanide, by the dehydration of an amide, by dehydration of oximes, or by other known procedures.
  • reaction (a) the other starting reactant is a l-aminoisoquinoline.
  • R was ethyl or butyl, but it can be other alkyl, aryl, or the like).
  • l-aminoisoquinolines containing alkoxy substituents are available through the corresponding 1- hydrazinoisoquinolines by reactions (e) and (h).
  • the corresponding l-hydrazinoisoquinolines are readily prepared by the known reaction of a l-chloroisoquinoline with hydrazine.
  • Many l-chloroisoquinolines are known.
  • a useful method for synthesizing l-chloroisoquinolines is to react an isocarbostyril with phosphorus oxychloride in accordance with the following reaction:
  • the reaction with hydrazine should be carried out in methanol.
  • the l-hydrazinoisoquinoline is formed first, and it then precipitates from solution thereby avoiding the preparation of poly-hydrazinoisoquinolines.
  • Reaction (a) is carried out by reacting a l-aminoisoquinoline with nitrile.
  • a Lewis acid catalyst is required for the reaction, although with some nitriles containing fluoro substituents on the alpha carbon atom, no catalyst is needed.
  • the Lewis acid catalysts used are compounds such as aluminum trichloride, titanium tetrachloride, tetraisopropyl titanate, boron trifluoride, and the like. Aluminum trichlon'de is preferred.
  • the catalyst is employed in catalytically elfective quantities, such as from about to 150 weight percent, and preferably from about 50 to 120 weight percent, based upon weight of the l-aminoisoquinoline.
  • the exact temperature to be used in the reaction depends in part, upon the nature of the reactants, and particularly upon the nature of the nitrile. For instance, when trifiuoroacetonitrile is used in reaction (a), the reaction proceeds at room temperature. With less reactive nitriles, higher temperatures are used. For instance, temperatures of from about 150 C. to about 210 C can be used, with temperatures of from about 175 to about 200 C. being preferred.
  • the reaction is conveniently carried out in an inert solvent either by adding catalyst to a solution of nitrile plus l-aminoisoquinoline, or by adding nitrile to a solution of l-aminoisoquinoline (either with or without a catalyst).
  • Suitable inert solvents include hydrocarbons such as benzene, toluene, xylene, naphthalene, methylnaphthalene, and the like.
  • the proportions of the reactants are not narrowly critical. About stoichiometric proportions can be used, although higher yields are obtained in most cases when excess nitrile is employed. It is therefore desirable to employ up to about 150 percent molar excess of nitrile.
  • the reaction can be carried out in conventional equipment at atmospheric pressure, or under super-atmospheric pressure in the event that the reaction is to be carried out at a temperature exceeding the boiling point of any of the reactants or solvent. In such cases, the reaction is preferably carried out in a closed vessel under autogenous pressure.
  • Reaction (a) is carried out for a period of time sufiicient to produce an N-(1-isoquinolyl)amidine.
  • the exact time selected will vary, to an extent, with the reaction temperature and the nature of the amidine. Usually, the higher temperature reactions are faster, for instance, from about /2 to about 5 hours, and preferably from about 2 to about 3 hours.
  • the amidine product is recovered by conventional procedures. For instance, the reaction mixture containing catalyst, product, and unreacted starting material can be poured into aqueous acid (such as hydrochloric acid) to form a water-soluble amidine salt. The solvent can then be decanted, after which the aqueous mixture can be cooled and alkali added to precipitate the organic materials (i.e., product and unreacted starting material).
  • the crude amidine can then be purified by dissolving it in diethyl ether, drying the ethereal solution, and evaporating the ether.
  • the amidine can be further purified by dissolving it in benzene and passing the benzene solution through a neutral aluminum oxide column. The unreacted starting ma- 8 terial is adsorbed in the column, and the pure amidine is recovered by evaporating the benzene.
  • the amidine can be recovered simply by evaporating the solvent. In some cases, it may also be desirable to pass a solution of the amidine through a neutral aluminum oxide column in order to remove unreacted starting material.
  • reaction (b) the amidine product of reaction (a) is contacted with lead tetraacetate to elfect ring closure and thereby produce an s-triazolo[5,l-a]isoquinoline.
  • This reaction is carried out simply by heating a mixture of the amidine and lead tetraacetate in a suitable solvent for a period of time sufiicient to effect ring closure.
  • the temperature can vary from about 75 C. to about C.
  • the reaction time will vary depending on the temperature, nature of the amidine, and the like, but in general will be from about 10 minutes to about 45 minutes.
  • a convenient way to carry out reaction (b) is to reflux a mixture of amidine and dry lead tetraacetate in a solvent having a suitable boiling point.
  • solvents include benzene, toluene, xylene, cyclohexane, glacial acetic acid, or mixtures thereof.
  • the lead tetraacetate is preferably used in at least stoichiometric proportions. For instance, from about 1.1 to about 2 moles of lead tetraacetate per mole of amidine is suitable in most cases.
  • the s-triazolo[5,1-a]isoquinoline product of reaction (b) can be recovered by conventional procedures. For instance, the cooled reaction mixture can be washed with aqueous alkali, and the product can be separated from the basic aqueous mixture as a solution in a hydrocarbon solvent such as benzene. After drying, the solvent can be removed by evaporation to yield the product. Further purification by recrystallization can be performed if desired.
  • R represents C C alkyl NaOH (q) as: ROH or 210m RCN ISO-250C- (v) non soc1 act
  • R represents C C alkyl NaOH (q) as: ROH or 210m RCN ISO-250C- (v) non soc1 act
  • s-triazolo[5,1-a]isoquinolines that can be produced by the above-exemplified reactions (j) through (2) are the following specific illustrative compounds:
  • N ON HONO Reaction (2) is a known type of reaction, although it had not heretofore been applied to l-hydrazinoisoquinolines.
  • the nitrous acid is generated in situ from alkali metal nitrite and an acid such as hydrochloric acid.
  • a suitable way to carry out the reaction is to first dissolve the l-hydrazinoisoquinoline in aqueous inorganic acid, such as hydrochloric acid. It may be necessary to warm the mixture in order to facilitate dissolution.
  • the solution is then cooled in an ice bath to about 15 to +10 C., and an aqueous solution of sodium nitrite is added in about stoichiometric proportions (i.e., about 1 to 1.1 moles of sodium nitrite per mole of l-hydrazinoisoquinoline).
  • the reaction mixture is then stirred for a short period of time, such as from about 15 to 30 minutes, and the product is recovered by filtration (the tetrazolo [5,1-a1isoquinoline is insoluble in water), and purified by recrystallization from an ethanol/water mixture.
  • the substituent groups in the tetrazolo[5,1-a]isoquinolines can be introduced by procedures that are known in the art. For instance, many substituted tetrazolo[5,1-a] isoquinolines can be prepared from known l-chloroisoquinolines that have the same substituent group. Examples of known l-chloroisoquinolines and the corresponding tetrazolo[5,1-a]isoquinolines produced therefrom include the following compounds:
  • reaction (1) When starting with :a dichloroisoquinoline, the reaction with hydrazine (i.e., Reaction (1) above) is preferably carried out in methanol, since the 1-hydrazinoisoquino line, which forms first, is very insoluble in methanol.
  • Some known isocarbostyrils, the l-chloroisoquinolines derived therefrom by reaction (i) above, and the tetrazolo [5,1-a]isoquinolines produced from the l-chloroisoquinolines via reactions (1) and (2) above, include the following:
  • Another way to prepare substituted tetraZolo[5,1-a]isoquinoline derivatives is to react a readily obtainable tetrazolo[5,l-a]isoquinoline (such as one containing one or more chloro substituents) in accordance with known reactions in order to introduce other substituent groups.
  • Such known reactions include reactions (1') through (2), above.
  • the product of a substitution reaction will have the substituent on the 5 position instead of the expected 6 position.
  • the reaction of 6-chlorotetrazolo[5,l-a]isoquinoline with sodium methoxide in methanol solvent yields S-methoxytetrazolo[5,1-a]isoquinoline instead of the expected 6-methoxy derivative.
  • reaction of the same 6-chloro compound with sodium methanethiolate in dimethyl sulfoxide solvent produces the expected 6-methylthiotetrazolo [5,1-a]isoquinoline.
  • tetrazolo[5,l-a]isoquinolines can employ a wide variety of tetrazolo[5,l-a]isoquinolines. Included are those compounds that can be prepared directly from readily available l-hydrazinoisoquinolines such as alkyl-, chloro-, alkoxy-, phenyl-, cyano-, and carbalkoxy substituted tertazolo[5,1-a]isoquinolines. These classes of compounds were exemplified by the specific compounds enumerated above. Additional tetraZolo[5,1-a]isoquinolines that are within the scope of the invention are those that can be produced by known types of reactions such as reactions (j) through (2), above. Specific illustrations of such tetrazolo[5,1-a]isoquinolines include the following compounds:
  • isoquinoline 7-[3-(N,N-dimethylamino)propylamino]tetrazolo[5, l-a] isoquinoline, 9-cyanotetrazolo[5,l-a]isoquinoline, S-aminoethyltetrazolo[5,1-a]isoquinoline,
  • the process of the invention selectively hydrogenates the triand tetrazoloisoquinolines in the 5,6 position.
  • the process comprises contacting the trior tetrazoloisoquinoline with hydrogen gas in the presence of a nickel, palladium, or platinum catalyst.
  • the hydrogenation reaction can be conveniently carried out in accordance with the following procedure:
  • the compound to be hydrogenated is charged to a conventional pressure vessel, such as an autoclave, along with an inert solvent such as ethanol or isopropyl alcohol.
  • a catalytic quantity of the hydrogenation catalyst is then added.
  • Useful catalysts include nickel, palladium, or platinum deposited on charcoal, with palladium-on-charcoal being preferred.
  • Useful catalytic quantities for one mole of the compound to be hydrogenated have been found to be from about 20 to 40 grams of a catalyst consisting of about 5 weight percent nickel, palladium or platinum-oncharcoal.
  • the autoclave is then flushed with hydrogen, sealed, and hydrogen gas is injected to a pressure of, for instance, over 20 atmospheres and up to atmospheres or more.
  • the autoclave is shaken to saturate the mixture, and additional hydrogen is added to bring the pressure back up.
  • the autoclave is then slowly heated from room temperature at a rate of, for example, about 20 C. per hour, and the pressure increase is plotted against time (or temperature).
  • the graph of pressure v. time or temperature will be very close to linear. (Hydrogenation of easily reducible substitutes such as nitro will occur first, and such reductions should be completed before plotting the graph).
  • the initiation of the hydrogenation reaction is detected by a somewhat lower rise than that which is extrapolated.
  • heating is reduced and the temperature is allowed to increase by about 10 C. and it is there stabilized.
  • the hydrogenation reaction rate will be about 0.01 mole per hour per gram of catalyst (catalyst refers to active metal plus charcoal, when metal catalyst deposited on charcoal is used as the catalyst). Reaction rate would increase by a factor of about 2 for a 10 C. rise in temperature.
  • the hydrogenation reaction is normally carried out at temperatures within the range of from about 50 to 160 C., and preferably from about 80 C. to C.
  • the hydrogenation reaction is followed by observing the pressure decrease. When the pressure stops decreasing, the reaction has stopped.
  • the hydrogenation is selective for the 5,6 position. Additional hydrogenation on the rings does not become significant until temperature is raised about 50 C. above the temperature at which reaction is first observed.
  • the hydrogenated product is recovered by standard procedures such as by filtration to separate the catalyst, evaporation of the solvent, and recrystallization from a convenient solvent such as ethanol, butanol, cyclohexane, benzene, ethanol/water, or the like. Yields are usually 80 percent or higher.
  • the process comprises reacting a trior tetrazoloisoquinoline with hydrogen in the presence of a hydrogenation catalyst at a temperature within the range of from about 50 to about 160 C., and preferably from about 80 to about 110 C., for a period of time sufficient to hydrogenate the 5,6 position of said trior tetrazoloisoquinoline, provided that the reaction temperature employed is not more than about 50 C. higher, and preferably not more than 30 C. higher, than the temperature at which the hydrogenation reaction begins.
  • the compounds that can be produced by the process of the invention are very useful. Because they are basic in nature, they can be used as hydrogen halide acceptors in processes such as the one disclosed in US. Pat. No. 3,071,- 605 for the production of cyclopentadienyl metal compounds.
  • the compounds can also be used as corrosion inhibitors in aqueous ethylene glycol-based cooling liquids.
  • the compounds that can be produced by the process of the invention which contain active hydrogen atoms can be reacted with ethylene oxide to form surface active agents useful as Wetting agents, detergents, and the like.
  • the compounds are also useful as reaction intermediates.
  • the temperature was allowed to increase to about 10 C. higher than the temperature at which the reaction was first detected.
  • the contents of the autoclave were then held at that temperature until the hydrogenation pressure stopped decreasing.
  • the autoclave was then cooled and vented, and the solvent was evaporated after filtering out the catalyst. Purification of the product, if necessary, was done by recrystallization.
  • the following materials were hydrogenated:
  • Example 1 8,9-dimethoxy-s-triazolo[3,4-a1isoquinoline was hydrogenated to 5,6-dihydro-8,9-dimethoxy-s-triazolo[3,4-a] isoquinoline, The reaction was first detected at 80 C., and was carried out at 90 C. The rate at 90 C. was about 54 mole/hour/gram of catalyst. The yield was close to 100% without recrystallization. Elemental analysis of the product was:
  • Example 2 3-methyl-s-triazolo[3,4-a1isoquinoline was hydrogenated to 5,6-dihydro-3-methyl-s-triazolo[3,4-a]isoquinoline.
  • the reaction was first detected at C., and it was carried out at C.
  • the rate at 90 C. was about 0.01 mole/hour/gram of catalyst.
  • the yield was about 80%.
  • the product was identified by comparison of the infrared spectrum with an authentic sample.
  • Example 3 s-Triazolo[3,4-a]isoquinoline was hydrogenated to 5,6- dihydro-s-triazolo[3,4 a]isoquinoline.
  • the conditions were analogous to Example 2. Elemental analysis of the product was:
  • Example 4 3-trifluorornethyl-s-triazolo[3,4-a]isoquinoline was hydrogenated to 5,6-dihydro-3-trifluoromethyl-s-triazolo [3,4-a]i.soquinoline by procedure and conditions analogous to Example 2.
  • the elemental analysis of the product was:
  • Example 5 To a 250 ml. autoclave were charged 10 grams tetrazolo[5,1-a]isoquinoline, milliliters of ethanol, and 1.5 grams of 5 weight percent palladium-on-charcoal (Type 16, from Johnson, Matthey & Co. Ltd.). The autoclave was flushed with hydrogen, sealed and filled with hydrogen at room temperature to about 88 kilograms per cm. pressure. The autoclave was slowly heated to 100 C. and held there until the hydrogen pressure levelled off. The autoclave was cooled and vented, and the solvent was evaporated.
  • Reaction rate at 90 C. was ,4 mole/ hour/gram of catalyst.
  • the autoclave was cooled and vented, and the solvent was evaporated. After recrystallization from benzene/cyclohexane, there was obtained 2- methyl-S,6-dihydro-s-triazolo[5,1 a]isoquinoline. M.P. 54-56 C. in 80 percent yield.

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Abstract

TRI- AND TETRAZOLOISOQUINOLINES, SUCH AS 3-AMINO-S-TRIAZOLO(3,4-A)ISOQUINOLINE OR 5 - METHYLTHIOTETRAZOLO(5,1-A) ISOQUINOLINE, ARE SELECTIVELY HYDROGENATED IN THE 5,6 POSITION AT A TEMPERATURE WITHIN THE RANGE OF FROM ABOUT 50* TO ABOUT 160*C. PROVIDED THAT THE TEMPERATURE SELECTED IS NOT MORE THAN ABOUT 50*C. HIGHER THAN THE TEMPERATURE AT WHICH HYDROGENATION IS FIRST OBSERVED, IN THE PRESENCE OF A CATALYTIC QUANITYT OF A NICKEL, PLATINUM, OR PALLADIUM HYDROGENATION CATALYST, FOR A PERIOD OF TIME AND AT A PRESSURE SUFFICIENT TO HYDROGENATE THE 5,6 POSITON.

Description

United States Patent 3,775,417 SELECTIVE HYDROGENATION F TRI- AND TETRAZOLOISOQUINOLINES Ernest H. de Rutter, Beersel, and Hans K. Reimlinger, Brussels, Belgium, assignors to Mallinckrodt Chemical Works, St. Louis, Mo. v No Drawing. Continuation of abandoned application Ser. No. 743,624, July 10, 1968. This application Aug. 5, 1971, Ser. No. 169,521
Int. Cl. C07d 55/06 US. Cl. 260-288 R 1 Claim ABSTRACT OF THE DISCLOSURE The invention relates to a process for selectively hydrogenating triand tetrazoloisoquinolines in the 5,6 position. More particularly, the process comprises contacting a trior tetrazoloisoquinoline with hydrogen in the presence of a nickel, palladium, or platinum catalyst under carefully controlled conditions, which is described herein below.
The triand tetrazoloisoquinolines that are selectively hydrogenated by the process of the invention are illustrated by the following three classes of compounds:
s-Triazo1o[5,1-a]isoquinolines, that have the following basic structure:
Tetrazolo[5,l-a]isoquinolines that have the following basic structure:
s-Triazolo[3,4 a]isoquinolineswhich have the following basic structure:
(III) In the foregoing formulas, the variables R R RVRS, R and R individuallycan represent substitutents such "ice amino, aminoalkylam-ino, dialkylaminoalkylamino, dialkylaminoalkoxy, hydroxy, sulfhydryl, alkylthio, cyano, haloalkyl, aminoalkyl, and the like, Preferred R through R variables include hydrogen, bromo, chloro, lower alkoxy and lower alkyl (i.e., C -C alkyl and alkoxy) especially methoxy, methyl, and ethyl, lower alkylthio especially methylthio, cyano, amino, dimethylarnino, diethylamino, Z-aminoethylamino, 3-aminopropylamino, 2- dimethylaminoethylamino, 3-dimethylaminopropylaming, 2-dimethylaminoethoxy, aminoethyl, and the like. Usually the R through R substituent group will contain not more than 20 carbon atoms, and preferably not more than 8 carbon atoms. The R variable can represent alkyl, alkaryl, aralkyl, aryl, amino, haloalkyl, cycloalkyl, heterocyclic groups (particularly 5- or 6-membered rings containing oxygen or nitrogen as the hetero atom), and alkoxyalkyl. Usually, R will contain not more than 20, and preferably not more than 10, carbon atoms. Preferred R variables are lower alkyl (i.e., C -C alkyl) and especially methyl, trifiuoromethyl, and phenyl. The R variable can be hydrogen, amino, or aliphatic, aromatic, cycloaliphatic, or heterocyclic groups containing up to 24 carbon atoms.
The hydrogenated products are compounds that can be represented by the formulas:
(Ir-h) (III-h) wherein the several R variables have the significance stated above with respect to Formulas I, II and III.
The s-triazolo[3,4,a]isoquinolines can be produced by reacting a l-hydrazinoisoquinoline with an acidic reagent such as an acyl halide, a carboxylic acid anhydride, an orthoformic ester, a carboxylic acid, carbon disulfide, cyanogen bromide, an isocyanate, or a urethane. Descriptions of processes for producing s-triazolo[3,4-a]isoquinoas hydrogen, alkyl, cycloalkyl, aryl, halo, amino, dialkyllines are found in copending application Ser. No. 634,077, filed Apr. 27, 1967 for s'-Triazolo[3,4-a]lsoquinolines and Derivatives Thereof by H. Reimlinger et al. (assigned to the same assignee as this application, now abandoned); in U.S. Patent No. 3,354,164; in an article by Naqui et al., Indian Journal of Chemistry 3, 162 (1965); and in an article by Sidhu et al., Journal of Heterocyclic Chemistry 3, 158-164 (.1966). I
' Illustrative s-triazolo[3,4-a]isoquinolines that can be used in the invention include, among others,
3-amino-s-triazolo[3,4-a]isoquinoline, 3 -aminoethyl-s-triazolo 3,4,-a] isoquinoline, 3-aminoethyl-s-triazolo[3,4-alisoquinoline, 3-(N,N-dimethy1aminoethyl)-s-triazolo[3,4-a]
isoquinoline, 3- N-methylaminomethyl) -s-triazolo[ 3,4-a] isoquinoline, 3 (N,N-diethylamino pro pyl) -s-triazolo [3,4-a]
isoquinoline 3- N,N-dimethylaminomethyl) -s-triazolo [3,4-a]
isoquinoline, 3 N,N-dimethylaminopropyl-s-triazolo [3,4-a]
isoquinoline, 3-trifluoromethyl-s-triazolo [3 ,4-a] iso quinoline, 3-chloroethyl-s-triazolo [3,4-a] isoquinoline, 3-hydroxyalkyl-striazolo[3,4-a]isoquinoline, 3-carboethoxy-s-triazolo [3,4-a] isoquinoline, 3 -carboethoxymethyl-s-triazolo[ 3 ,4-a] isoquinoline, 3-(N-methylcarbamido)-s-triazolo[3,4-a1isoquinoline, 3-(N-methylamidomethyl)-s-triazolo[3,4-a]isoquinoline, 3 N-ethylamidomethyl) -s-triazolo 3,4-a] iso quinoline, 3-(N,N-dimethylamidomethyl)-s-triazolo[3,4-a]
isoquinoline, 3-hydroxy-S-methyl-s-triazolo[3,4a]isoquinoline, 3,5-dimethyl-s-triazolo[3,4-a]isoquinoline, S-methyl-s-triazolo [3 ,4-a] isoquinoline, S-carboethoxy-S-chloro-s-triazolo [3,4-a1isoquinoline, S-chloro-s-triazolo 3,4-a] isoquinoline, 3-benzy1amidomethyl-S-chloro-s-triazolo[3,4-a]
isoquinoline, 3-carboethoxymethyl-5-chloro s-triazolo[3,4-a]
isoquinoline, S-methoxy-s-tn'azolo [3,4-a] isoquinoline, 3-benzylarnido-54benzylamino-s-triazolo[3,4-a]
isoquinoline, 5- (N-piperidyl) -s-triazolo 3 ,4-a] isoquinoline, 3-methy1-6-chloro -s-triazo1o [3 ,4-a] isoquinoline, 3-trifluoromethyl-6-chloro-s-triazolo [3 ,4-a] isoquinoline, 3-methylthio-6-chloro-s-triazolo 3 ,4-a] isoquinoline, 6-chloro-3-carboethoxymethyl-s-triazolo[3,4-a]
isoquinoline, 3-thio-6-chloro-s-triazolo[3,4-a]isoquino1ine, 3-ethylthio 6-chloro-s-triazolo[3,4a]isoquinoline, 3 -b enzoylaminomethyl-6-chloro-s-triazolo 3,4-a]
isoquinoline, S-(a-aminoethyl -6-chloro-s-triazolo [3,4-a] isoquinoline, 3-(a-aminopropyl)-6-chloro-s-triazolo[3,4-a1isoquinoline, 3-benzylcarbamidoethyl-6-chloro-s-triazolo[3,4-a]
isoquinoline, 3-( l-benzylcarbamido-Z-methylethyl) -6-chloro-striaz0lo[ 3,4-a] isoquinoline, 6-chloro-s-triazolo[3,4-a1isoquinoline, 6-bromo-s-triaz0lo[3,4-a]isoquinoline, 6-methyl-s-triazolo[3,4-a1isoquinoline, 6-cyano-s-triazolo[3,4-a]isoquinoline, 3-trifluoromethyl-6-cyano-s-triazolo[3,4-a]isoquinoline, 6-m'tro-s-triazolo [3,4a] isoquinoline, 6-amido-s-triazolo [3 ,4-a] isoquinoline, 3-carbomethoxy-6-chloro-s-triazolo[3,4-a]isoquinoline, 8,9-dimethoxy-s-triazolo[3,4-a]isoquinoline, 3-trifluoromethyl-8,9-dimethoxy-s-triazolo 3,4-a]
isoquinoline, v 6-chloro-8,9-dimethoxy-s-triazolo[3,4-a]isoquinoline, 3-trifluoromethyl-6-chloro-8,9-dimethoxy-s-triazolo [3,4-a]isoquinoline, 7-nitro-s-triazolo[3,4-a]isoquinoline, 7-amino-s-triazolo[3,4-a]isoquinoline hydrochloride, 7-nitro-6-hydroxy-s-triazolo[3,4-a]isoquinoline,
and the like. '1
The s-triazolo[5,l-a]isoquinolines can be produced by the following sequence of reactions, starting with known types of reactants:
(a) A rl-aminoisoquinoline is reacted with a nitrile to produce an N-(l-isoquinolinyDamidine;
(b) The N-(l-isoquinolyl)amidine is then contacted with lead tetraacetate to effect ring closure and thereby produce the s-triazolo[5,1-a]isoquinoline:
Reaction (a) is carried out by reacting a l-aminoisoquinoline with a nitrile. Ordinarily, a Lewis acid catalyst is used, although in some cases, no catalyst is needed. The nitriles that are used are compounds of the formula:
1 R2CN where R represents alkyl, alkaryl, aralkyl, aryl, haloalkyl, cycloalkyl, heterocyclic groups, alkoxyalkyl groups, and the like.
Specific illustrative nitriles that can be used in the invention include the following compounds:
acetonitn'le, decanenitrile, propionitrile, dodecanenitrile, butyronitrile, tetradecanem'trile, valeronitrile, hexadecanenitrile, hexanenitrile, octadecanenitrile, heptanenitrile, eicosanenitrile, octanenitrile,
and other alkanenitriles having up to 20 carbon atoms. The preferred alkanenitriles are those having up to six carbon atoms, and those having from two to four carbon atoms are more preferred.
Other useful nitriles include the aromatic and cycloalkyl nitriles such as the following compounds:
benzom'trile,
cyclohexanenitrile, cyclopcntanenitrile, p-methylbenzonitrile, phenylacetonitrile (benzyl cyanide), a-phenylbutyronitrile,
and the like.
Other useful nitriles include the haloalkyl nitriles such as the following compounds:
chloroacetonitrile, trichloroacetonitrile, trifluoroacetonitrile, fiuoroacetonitrile, B-chloropropionitrile, B-bromopropionitrile, 'y-chlorobutyronitrile, a-chloroisobutyronitrile,
and the like.
Still other useful nitriles include the heterocyclic nitriles such as the following compounds:
The nitriles that are employed in the invention are a well known class of compounds that can be obtained by known procedures. Nitriles are readily prepared, for instance, by reaction of benzyl chlorides or primary or secondary alkyl chlorides with alkali metal cyanide, by reaction of potassium arylsulfonic acid salts with potassium cyanide, by the dehydration of an amide, by dehydration of oximes, or by other known procedures.
In reaction (a), the other starting reactant is a l-aminoisoquinoline. These compounds can be obtained by the following types of reactions:
(c) The known reaction of unsubstituted isoquinoline or hydrocarbyl-substituted isoquinolines with sodium amide in liquid ammonia:
(d) The known reaction of 1,3-dichloroisoquinolines with alcoholic ammonia at 180 0.:
GN NHa in ethanol ON (e) The known reduction of a l-hydrazinoisoquinoline (prepared by reacting a l-chloroisoquinoline with hydrazine) with hydrogen using a palladium catalyst:
(in the published cases, R was ethyl or butyl, but it can be other alkyl, aryl, or the like).
(f) Reaction of a l-methoxyisoquinoline with sodium amide and liquid ammonia at atmospheric pressure in refluxing toluene:
(I) 0 Ha IIIHz 0N NaNHz, NHa 0N Refiuxing toluene I 01 (h) l-aminoisoquinolines having alkoxy substituents in the benzene ring or other easily reducible substituents can be produced by the following sequence of reactions:
w N CaHi IIIHNHZ CH3O N Acetophenone CH3O NH on o H20 CH 0 I 3 a t 0 l /N C5115 i ITIH CH5O NH Zinc dust in CHQO 6N CH30 acetic acid CHaO room temperature The foregoing techniques can be used to prepare a wide variety of l-aminoisoquinolines. Unsubstituted and hydrocarbyl-substituted l-aminoisoquinolines are readily available via reaction (c). l-aminoisoquinolines containing chloro substituents are readily available via reactions (d) or (f). 1-amino-4-nitroisoquinolines can be produced by reaction (g). l-aminoisoquinolines containing alkoxy substituents are available through the corresponding 1- hydrazinoisoquinolines by reactions (e) and (h). The corresponding l-hydrazinoisoquinolines are readily prepared by the known reaction of a l-chloroisoquinoline with hydrazine. Many l-chloroisoquinolines are known. A useful method for synthesizing l-chloroisoquinolines is to react an isocarbostyril with phosphorus oxychloride in accordance with the following reaction:
In preparing a l-hydrazinoisoquinoline from a 1-chloroisoquinoline that contains additional chloro substituents, the reaction with hydrazine should be carried out in methanol. The l-hydrazinoisoquinoline is formed first, and it then precipitates from solution thereby avoiding the preparation of poly-hydrazinoisoquinolines.
Among the 1-aminoisoquinolines that can be used in reaction (a) are the following compounds:
Reaction (a) is carried out by reacting a l-aminoisoquinoline with nitrile. In most cases, a Lewis acid catalyst is required for the reaction, although with some nitriles containing fluoro substituents on the alpha carbon atom, no catalyst is needed. The Lewis acid catalysts used are compounds such as aluminum trichloride, titanium tetrachloride, tetraisopropyl titanate, boron trifluoride, and the like. Aluminum trichlon'de is preferred. The catalyst is employed in catalytically elfective quantities, such as from about to 150 weight percent, and preferably from about 50 to 120 weight percent, based upon weight of the l-aminoisoquinoline.
With some nitriles having one or more fluoro substituents on the alpha carbon atom, no catalyst is needed. For instance, when trifluoroacetonitrile is used in reaction (a), no catalyst is required.
The exact temperature to be used in the reaction depends in part, upon the nature of the reactants, and particularly upon the nature of the nitrile. For instance, when trifiuoroacetonitrile is used in reaction (a), the reaction proceeds at room temperature. With less reactive nitriles, higher temperatures are used. For instance, temperatures of from about 150 C. to about 210 C can be used, with temperatures of from about 175 to about 200 C. being preferred.
The reaction is conveniently carried out in an inert solvent either by adding catalyst to a solution of nitrile plus l-aminoisoquinoline, or by adding nitrile to a solution of l-aminoisoquinoline (either with or without a catalyst). In any event, it is desirable to avoid adding nitrile to catalyst without a l-aminoisoquinoline being present in order to avoid trimerization of the nitrile to an s-triazine which will reduce the yields of the desired amidine product of reaction (a).
Suitable inert solvents include hydrocarbons such as benzene, toluene, xylene, naphthalene, methylnaphthalene, and the like.
The proportions of the reactants are not narrowly critical. About stoichiometric proportions can be used, although higher yields are obtained in most cases when excess nitrile is employed. It is therefore desirable to employ up to about 150 percent molar excess of nitrile.
The reaction can be carried out in conventional equipment at atmospheric pressure, or under super-atmospheric pressure in the event that the reaction is to be carried out at a temperature exceeding the boiling point of any of the reactants or solvent. In such cases, the reaction is preferably carried out in a closed vessel under autogenous pressure.
Reaction (a) is carried out for a period of time sufiicient to produce an N-(1-isoquinolyl)amidine. The exact time selected will vary, to an extent, with the reaction temperature and the nature of the amidine. Usually, the higher temperature reactions are faster, for instance, from about /2 to about 5 hours, and preferably from about 2 to about 3 hours. The reactions that are carried out at low temperatures, e;g., those wherein the nitrile is activated by fluoro substituents or the alpha carbon atom, normally are slower. For instance, reaction times of up to 100 hours, and preferably from about 25 to about 80 hours, can be employed.
The amidine product is recovered by conventional procedures. For instance, the reaction mixture containing catalyst, product, and unreacted starting material can be poured into aqueous acid (such as hydrochloric acid) to form a water-soluble amidine salt. The solvent can then be decanted, after which the aqueous mixture can be cooled and alkali added to precipitate the organic materials (i.e., product and unreacted starting material). The crude amidine can then be purified by dissolving it in diethyl ether, drying the ethereal solution, and evaporating the ether. The amidine can be further purified by dissolving it in benzene and passing the benzene solution through a neutral aluminum oxide column. The unreacted starting ma- 8 terial is adsorbed in the column, and the pure amidine is recovered by evaporating the benzene.
In cases Where no Lewis acid catalyst is used, it is not necessary to use water extraction. In many cases, the amidine can be recovered simply by evaporating the solvent. In some cases, it may also be desirable to pass a solution of the amidine through a neutral aluminum oxide column in order to remove unreacted starting material.
In the second step for producing the s-triazolo[5,l-a] isoquiuolines of the invention, i.e., reaction (b), the amidine product of reaction (a) is contacted with lead tetraacetate to elfect ring closure and thereby produce an s-triazolo[5,l-a]isoquinoline. This reaction is carried out simply by heating a mixture of the amidine and lead tetraacetate in a suitable solvent for a period of time sufiicient to effect ring closure. The temperature can vary from about 75 C. to about C. The reaction time will vary depending on the temperature, nature of the amidine, and the like, but in general will be from about 10 minutes to about 45 minutes.
A convenient way to carry out reaction (b) is to reflux a mixture of amidine and dry lead tetraacetate in a solvent having a suitable boiling point. Such solvents include benzene, toluene, xylene, cyclohexane, glacial acetic acid, or mixtures thereof.
The lead tetraacetate is preferably used in at least stoichiometric proportions. For instance, from about 1.1 to about 2 moles of lead tetraacetate per mole of amidine is suitable in most cases.
The s-triazolo[5,1-a]isoquinoline product of reaction (b) can be recovered by conventional procedures. For instance, the cooled reaction mixture can be washed with aqueous alkali, and the product can be separated from the basic aqueous mixture as a solution in a hydrocarbon solvent such as benzene. After drying, the solvent can be removed by evaporation to yield the product. Further purification by recrystallization can be performed if desired.
Among the s-triazolo[5,1-a]isoquinolines that can be produced, by the sequence of reactions (a) and (b) described above, from known and/or readily available nitriles and l-aminoisoquinolines, are the following specific illustrative compounds:
Z-methyl-s-triazolo [5 l -a] isoquinoline, 2-ethyl-striazolo [5 l-a] isoquinoline, 2-propyl-s-triazolo [5, l-a] isoquinoline, 2-butyl-s-triazolo [5 l-a] isoquinoline, 2-pentyl-s-triazolo[5,1-a]isoquinoline, 5-chloro-2-methyl-s-triazolo[5,1-a]isoquinolinc, 6-chloro-2-methyl-s-triazolo [5 l-a] iso quinoline, 2,5-dimethyl-s-triazolo[5,1-a]isoquinoline, 2,5-dimethyl-6-cyano-s-triazolo[5,1-a]isoquinoline, 9-chloro-2-methyl-s-triazolo [5, l-a] isoquinoline, 2-ethyl-6-nitro-s-triazolo [5,1-a] isoquinoline, 6-ethoxy-2-methyl-s-triazolo [5, l-a] isoquinoline, 6-butoxy-Z-hexyl-s-triazolo [5 l-a] isoquinoline, 7-methoxy-2-methyl-s-triazolo [5, l-a] isoquinoline, 8-methoxy-2-methyl-s-triazolo [5 l-a] isoquinoline, 9-methoxy-2-methyl-s-triazolo[5,1-a]isoquinoline, 8,9-dimethoxy-2-methyl-s-triazolo [5 l-a] isoquinoline, 7 ,8,9-trimethoxy-Z-methyl-s-triazolo [5 1-a] isoquinoline,
and other Z-alkyl-s-triazolo [5,1-a]isoquinolines.
Other illustrative compounds include:
2-phenyl-s-triazolo [5, 1-a]isoquinoline, Z-cyclohexyl-s-triazolo [5 1-a]is0quinoline, 2-cyclopenty1-s-triazolo [5,l-a1isoquinoline, 2-tolyl-s-triazolo[5,1-a]isoquinoline, Z-phenylmethyl-s-triazolo [5, l-a] isoquinoline, 5-chloro-2-phenyl s-triazolo [5,1-a]isoquinoline, 6-chloro-2-phenyl-s-triazolo [5,1-a] isoquinoline, 8-methoxy-2-phenyl-s-triazolo [5 l-a] isoquinoline,
and other 2-aryl-, 2-cycloalkyl-, 2-alkaryl-, and 2-aralkyls-triazolo[5,1-a]isoquinolines.
Additional specific illustrative compounds include:
2-trifluoromethyl-s-triazolo l-a] isoquinoline,
Z-chIoromethyI-s-triazolo [5, 1-a]isoquinoline,
2-trichloromethyl s-triazolo 5 l-a] iso quiuoline,
Z-fluoromethyl-s-triazolo [5, l-a] isoquinoline,
2- (beta-chloroethyl) -s-triazo1o[5,1-a] isoquinoline,
2-(gamma-chloropropyl)-s-triazolo[5,1-a]isoquinoline,
7,8,9-trimethoxy-Z-trifluoromethyl-s-triazolo[5,1-a]
isoquinoline,
6-nitro-2-trifluoromethyl-s-triazolo [5,1-a]isoquinoline,
and other 2-haloalkyl-s-triazolo[5,1-a]isoquinolines.
Further illustrative compounds include:
Z-methoxymethyl-s-triazolo [5, 1-a] iso quinoline,
2- (beta-methoxyethyl) -s-triazolo [5,1-a] iso quinoline, Z-ethoxymethyl-s-triazolo [5 1-a]isoquinoline, 2-(Z-pyridyl)-s-triazolo[5,1-a]isoquinoline,
and the like.
Another way to prepare substituted s-triazolo[5,l-a] isoquinoline derivatives is to react a readily obtainable s-triazolo[5,1-a]isoquinoline (such as one containing one or more chloro substituents) in accordance with known reactions inorder to introduce other substituent groups. The following reactions, wherein R represents an s-triazolo[S,1-a]isoquinolyl group, are illustrative:
wherein R represents C C alkyl NaOH (q) as: ROH or 210m RCN ISO-250C- (v) non soc1 act Among the s-triazolo[5,1-a]isoquinolines that can be produced by the above-exemplified reactions (j) through (2) are the following specific illustrative compounds:
2-methyl-S-dimethylamino-s-triazolo [5,1-a] iso quinoline, 2-trifluoromethyl-9- 3 -aminoprop y1amin0)striazolo- [5,1-a]isoquinoline,
G1 I as @(r (2) A l-hydrazinoisoquinoline is reacted with nitrous acid to produce the tetrazolo[5,1-a]isoquinolines of the invention:
N ON HONO Reaction (2) is a known type of reaction, although it had not heretofore been applied to l-hydrazinoisoquinolines. In the usual case, the nitrous acid is generated in situ from alkali metal nitrite and an acid such as hydrochloric acid. A suitable way to carry out the reaction is to first dissolve the l-hydrazinoisoquinoline in aqueous inorganic acid, such as hydrochloric acid. It may be necessary to warm the mixture in order to facilitate dissolution. The solution is then cooled in an ice bath to about 15 to +10 C., and an aqueous solution of sodium nitrite is added in about stoichiometric proportions (i.e., about 1 to 1.1 moles of sodium nitrite per mole of l-hydrazinoisoquinoline). The reaction mixture is then stirred for a short period of time, such as from about 15 to 30 minutes, and the product is recovered by filtration (the tetrazolo [5,1-a1isoquinoline is insoluble in water), and purified by recrystallization from an ethanol/water mixture.
The substituent groups in the tetrazolo[5,1-a]isoquinolines can be introduced by procedures that are known in the art. For instance, many substituted tetrazolo[5,1-a] isoquinolines can be prepared from known l-chloroisoquinolines that have the same substituent group. Examples of known l-chloroisoquinolines and the corresponding tetrazolo[5,1-a]isoquinolines produced therefrom include the following compounds:
1,3-dichloroisoquinoline to produce S-chlorotetrazolo [5,1-a]isoquinoline,
1,4-dichloroisoquinoline to produce 6-chlorotetrazolo [5,1-a]isoquinoline,
When starting with :a dichloroisoquinoline, the reaction with hydrazine (i.e., Reaction (1) above) is preferably carried out in methanol, since the 1-hydrazinoisoquino line, which forms first, is very insoluble in methanol.
Thus, by precipitation of the l-hydrazino compound, the preparation of dihydrazino derivatives is avoided.
and the like.
Some known isocarbostyrils, the l-chloroisoquinolines derived therefrom by reaction (i) above, and the tetrazolo [5,1-a]isoquinolines produced from the l-chloroisoquinolines via reactions (1) and (2) above, include the following:
to produce 7-methoxyto produce 8-methoxyto produce 9-methoxyproduce S-ethyltetrazolo 5,6,7-trimethoxyisocarbostyril, 1-chloro-5,6,7-trimethoxyisoquinoline, and 7,8,9-trimethoxytetrazolo[5,1-a]isoquinoline, 6,7-dimethoxyisocarbostyril, l-chloro-6,7-dimethoxyisocarbostyril, and 8,9-dimethoxytetrazolo[5,1-a]isoquinoline, 3-methyl-4-cyanoisocarbostyril, l-chloro-3-methyl-4-cyanoisoquinoline, and -methyl-6-cyanotetrazolo[5,1-a]isoquinoline, 4-carbethoxyisocarbostyril, 1-chloro-4-carbethoxyisoquinoline, and 6-carbethoxytetrazolo[5,1-a1isoquinoline,
and the like.
Another way to prepare substituted tetraZolo[5,1-a]isoquinoline derivatives is to react a readily obtainable tetrazolo[5,l-a]isoquinoline (such as one containing one or more chloro substituents) in accordance with known reactions in order to introduce other substituent groups. Such known reactions include reactions (1') through (2), above.
In some cases when the halo group is in the 6 position on the tetrazolo[5,1-a]isoquinoline nucleus, the product of a substitution reaction will have the substituent on the 5 position instead of the expected 6 position. For instance, the reaction of 6-chlorotetrazolo[5,l-a]isoquinoline with sodium methoxide in methanol solvent yields S-methoxytetrazolo[5,1-a]isoquinoline instead of the expected 6-methoxy derivative. However, reaction of the same 6-chloro compound with sodium methanethiolate in dimethyl sulfoxide solvent produces the expected 6-methylthiotetrazolo [5,1-a]isoquinoline.
From the foregoing discussion, it is seen that the invention can employ a wide variety of tetrazolo[5,l-a]isoquinolines. Included are those compounds that can be prepared directly from readily available l-hydrazinoisoquinolines such as alkyl-, chloro-, alkoxy-, phenyl-, cyano-, and carbalkoxy substituted tertazolo[5,1-a]isoquinolines. These classes of compounds were exemplified by the specific compounds enumerated above. Additional tetraZolo[5,1-a]isoquinolines that are within the scope of the invention are those that can be produced by known types of reactions such as reactions (j) through (2), above. Specific illustrations of such tetrazolo[5,1-a]isoquinolines include the following compounds:
5 -methylthiotetrazolo [5 l-a] isoquinoline, 6-methylthiotetrazolo 5, l-a] isoquinoline, 6-carbethoxytetrazolo[5,1-a]isoquinoline, 5-(N-morpholino)tetrazolo[5,1-a]isoquinoline,
12 5-(N,N-dimethylamino)tetrazolo[5,1-a]isoquinoline, 8 [2 (N,N dimethylamino)ethoxy]tetrazolo[5,1-a]
isoquinoline, 7-[3-(N,N-dimethylamino)propylamino]tetrazolo[5, l-a] isoquinoline, 9-cyanotetrazolo[5,l-a]isoquinoline, S-aminoethyltetrazolo[5,1-a]isoquinoline,
and the like.
The preferred tetrazolo[5,1-a]isoquinolines include unsubstituted tetrazolo[5,1-a]isoquinoline and those compounds containing lower alkyl, lower =alkoxy, chloro, amino, N,N-dialkylamino, lower alkylthio, aminoalkylamino, and aminoalkoxy groups. It is also preferred that the alkyl moieties in said groups contain from 1 to 4 carbon atoms.
The process of the invention selectively hydrogenates the triand tetrazoloisoquinolines in the 5,6 position. Broadly, the process comprises contacting the trior tetrazoloisoquinoline with hydrogen gas in the presence of a nickel, palladium, or platinum catalyst. The hydrogenation reaction can be conveniently carried out in accordance with the following procedure:
The compound to be hydrogenated is charged to a conventional pressure vessel, such as an autoclave, along with an inert solvent such as ethanol or isopropyl alcohol. A catalytic quantity of the hydrogenation catalyst is then added. Useful catalysts include nickel, palladium, or platinum deposited on charcoal, with palladium-on-charcoal being preferred. Useful catalytic quantities for one mole of the compound to be hydrogenated have been found to be from about 20 to 40 grams of a catalyst consisting of about 5 weight percent nickel, palladium or platinum-oncharcoal. (The weight refers to active metal catalyst plus charcoal, not to active metal catalyst alone.) The autoclave is then flushed with hydrogen, sealed, and hydrogen gas is injected to a pressure of, for instance, over 20 atmospheres and up to atmospheres or more. The autoclave is shaken to saturate the mixture, and additional hydrogen is added to bring the pressure back up. The autoclave is then slowly heated from room temperature at a rate of, for example, about 20 C. per hour, and the pressure increase is plotted against time (or temperature). Before the hydrogenation of the 5,6 position starts, the graph of pressure v. time or temperature will be very close to linear. (Hydrogenation of easily reducible substitutes such as nitro will occur first, and such reductions should be completed before plotting the graph). The initiation of the hydrogenation reaction is detected by a somewhat lower rise than that which is extrapolated. When the reaction starts, heating is reduced and the temperature is allowed to increase by about 10 C. and it is there stabilized. At this temperature, the hydrogenation reaction rate will be about 0.01 mole per hour per gram of catalyst (catalyst refers to active metal plus charcoal, when metal catalyst deposited on charcoal is used as the catalyst). Reaction rate would increase by a factor of about 2 for a 10 C. rise in temperature.
The hydrogenation reaction is normally carried out at temperatures within the range of from about 50 to 160 C., and preferably from about 80 C. to C. The hydrogenation reaction is followed by observing the pressure decrease. When the pressure stops decreasing, the reaction has stopped.
Under the conditions described above, the hydrogenation is selective for the 5,6 position. Additional hydrogenation on the rings does not become significant until temperature is raised about 50 C. above the temperature at which reaction is first observed.
The hydrogenated product is recovered by standard procedures such as by filtration to separate the catalyst, evaporation of the solvent, and recrystallization from a convenient solvent such as ethanol, butanol, cyclohexane, benzene, ethanol/water, or the like. Yields are usually 80 percent or higher.
From the foregoing description of a convenient way for carrying out the process of the invention, it is seen that the process can be described as follows:
The process comprises reacting a trior tetrazoloisoquinoline with hydrogen in the presence of a hydrogenation catalyst at a temperature within the range of from about 50 to about 160 C., and preferably from about 80 to about 110 C., for a period of time sufficient to hydrogenate the 5,6 position of said trior tetrazoloisoquinoline, provided that the reaction temperature employed is not more than about 50 C. higher, and preferably not more than 30 C. higher, than the temperature at which the hydrogenation reaction begins.
Among the 5,-6-dihydrotetrazolo[5,1-a1isoquinolines that can be produced by the invention are the following compounds:
5,6-dihydrotetrazolo[5,1-a]isoquinoline, 8,9-dimethxy-5 ,6 -dihydrotetrazolo[ 1-a]isoquinoline, 5-chloro-5,6-dihydrotetrazolo[5,1-a] isoquinoline, 6-chloro-5,6-dihydrotetrazolo [5, l-a] isoquinoline, 9-chloro-5,6-dihydrotetrazolo [5, l-a] isoquinoline, 7-methoxy-5, 6- dihydrotetr azolo [5 1-a]isoquinoline, 5-ethy1-5,6-dihydrotetrazolo 5, l-a] isoquinoline,
5 -methylthio-5 ,G-dihydrotetrazolo [5 l-a] isoquinoline,
[5,1-a1isoquinoline,
as well as the 5,6-dihydro derivatives of the starting reactants enumerated above.
Among the 5,6-dihydro-s-triazolo[5,1-a]isoquinolines that are provided by the process of the invention are the following specific illustrative compounds:
Z-methyl-S,6-dihydro-s-triazolo 5, 1-a]isoquinoline,
Z-trifluoromethyl-5,6-dihydro-s-triazolo[5,1-a]isoquinoline 2-pheriyl-5,6-dihydro-s-triazolo [5,1-a]isoquinoline,
8,9-dirnethoxy-2-methyl-5,6-dihydro-s-triazolo [5,1 a] isoquinoline,
5-chloro-2-trifluoromethyl-S,6-dihydro-s-triazolo[5,1 a]
isoquinoline,
6-chloro-2-methyl-5,6-dihydro-s-triazolo-[5,1-a]isoquinoline,
9-chloro-2-phenyl-5,fi-dihydro-s-triazolo[5,1 a]isoquinoline,
5-methylthio-2-methyl-5,6-dihydro-s-triazolo[5,1 a]isoquinoline,
9- [2- (N,N-dimethylamino) ethoxy] -2-methyl-5,6-dihydros-triazolo[5,1-a] isoquinoline,
and the 5,6-dihydro derivatives of each of the starting reactants enumerated above.
Among the 5,6-dihydro-s-triazolo[3,4a]isoquinolines that can be produced by the process of the invention are the following illustrative compounds:
5 ,6-dihydro-s-triazolo[3,4-a]isoquinoline,
5 ,6 -dih'ydro-3-trifluoromethyl-s-tri azolo 3,4-a]isoquinoline,
5 6-dihydro-8,9-dirnethoxy-s-triazolo 3,4-a] isoquinoline,
5,6-dihydro-3-methyl-s-triazolo [3 ,4-a1isoquinoline,
as well as the 5,6-dihydro derivatives of each of the starting reactants enumerated above.
The compounds that can be produced by the process of the invention are very useful. Because they are basic in nature, they can be used as hydrogen halide acceptors in processes such as the one disclosed in US. Pat. No. 3,071,- 605 for the production of cyclopentadienyl metal compounds. The compounds can also be used as corrosion inhibitors in aqueous ethylene glycol-based cooling liquids. The compounds that can be produced by the process of the invention which contain active hydrogen atoms can be reacted with ethylene oxide to form surface active agents useful as Wetting agents, detergents, and the like. The compounds are also useful as reaction intermediates.
The examples appearing below illustrate the invention.
1 4 STANDARDIZED CONDITIONS In the examples, the following standardized procedure and conditions were used, unless otherwise indicated:
To a 250-milliliter autoclave was charged 0.05 mole of the trior tetrazoloisoquinoline to be hydrogenated, 100 milliliters of isopropyl alcohol, and 1.5 grams of 5 weight percent palladium-on-charcoal (Type 16, from Johnson, Matthey & Co. Ltd.). The autoclave was flushed with hydrogen, sealed and filled with hydrogen at room temperature to a pressure of about atmospheres. The autoclave was then shaken in order to saturate the liquid, and additional hydrogen was added to restore the pressure to 80 atmospheres. The autoclave was slowly heated (at a rate of about 20 C. per hour) and the pressure increase was plotted against time. The beginning of the reaction was detected by a somewhat slower pressure rise than that which was extrapolated. The temperature was allowed to increase to about 10 C. higher than the temperature at which the reaction was first detected. The contents of the autoclave were then held at that temperature until the hydrogenation pressure stopped decreasing. The autoclave was then cooled and vented, and the solvent was evaporated after filtering out the catalyst. Purification of the product, if necessary, was done by recrystallization. The following materials were hydrogenated:
Example 1 8,9-dimethoxy-s-triazolo[3,4-a1isoquinoline was hydrogenated to 5,6-dihydro-8,9-dimethoxy-s-triazolo[3,4-a] isoquinoline, The reaction was first detected at 80 C., and was carried out at 90 C. The rate at 90 C. was about 54 mole/hour/gram of catalyst. The yield was close to 100% without recrystallization. Elemental analysis of the product was:
Calculated (percent): C, 62.32; H, 5.67; N, 18.17; 0, 13.84. Found (percent): C, 62.11; H, 5.70; N, 17.64; 0, 14.43.
Example 2 3-methyl-s-triazolo[3,4-a1isoquinoline was hydrogenated to 5,6-dihydro-3-methyl-s-triazolo[3,4-a]isoquinoline. The reaction was first detected at C., and it was carried out at C. The rate at 90 C. was about 0.01 mole/hour/gram of catalyst. The yield was about 80%. The product was identified by comparison of the infrared spectrum with an authentic sample.
Example 3 s-Triazolo[3,4-a]isoquinoline was hydrogenated to 5,6- dihydro-s-triazolo[3,4 a]isoquinoline. The conditions were analogous to Example 2. Elemental analysis of the product was:
Calculated (percent): C, 70.15; H, 5.30; N, 24.55. Found (percent): C, 69.87; H, 5.29; N, 24.32.
Example 4 3-trifluorornethyl-s-triazolo[3,4-a]isoquinoline was hydrogenated to 5,6-dihydro-3-trifluoromethyl-s-triazolo [3,4-a]i.soquinoline by procedure and conditions analogous to Example 2. The elemental analysis of the product was:
Calculated (percent): C, 55.21; H, 3.37; N, 17.56. Found (percent): C, 55.03; H, 3.55; N, 17.27.
Example 5 To a 250 ml. autoclave were charged 10 grams tetrazolo[5,1-a]isoquinoline, milliliters of ethanol, and 1.5 grams of 5 weight percent palladium-on-charcoal (Type 16, from Johnson, Matthey & Co. Ltd.). The autoclave was flushed with hydrogen, sealed and filled with hydrogen at room temperature to about 88 kilograms per cm. pressure. The autoclave was slowly heated to 100 C. and held there until the hydrogen pressure levelled off. The autoclave was cooled and vented, and the solvent was evaporated. After recrystallization from benzene/ cyclohexane, there was obtained 6 grams of 5,6-dihydrotetrazolo[5,l-a]isoquinoline, M.P. 96 C Example 6 To a 250 ml. autoclave were charged 0.05 mole 2- methyl-s-triazolo[5,1-a]isoquinoline, 100 milliliters of isopropanol, and 1.5 grams of 5 weight percent palladiumon-charcoal (Type 16, from Johnson, Matthey & Co. Ltd.). The autoclave was flushed with hydrogen, sealed and filled with hydrogen at room temperature to about 88 kilograms per cm. pressure. The autoclave was slowly heated to 90 C. and held there until the hydrogen pressure levelled off. Reaction rate at 90 C. was ,4 mole/ hour/gram of catalyst. The autoclave was cooled and vented, and the solvent was evaporated. After recrystallization from benzene/cyclohexane, there was obtained 2- methyl-S,6-dihydro-s-triazolo[5,1 a]isoquinoline. M.P. 54-56 C. in 80 percent yield.
Elemental analysis: Calculated (percent): C, 71.33; H, 5.99; N, 22.69. Found (percent): C, 71.44; H, 6.12; N, 22.83.
What is claimed is:
1. The process of preparing 5,6-dihydro-3-trifluoromethyl-s-triazolo[3,4-a]isoquinoline by reacting hydrogen with 3-trifluoromethyl-s-triazolo[3,4-a]isoquinoline at a References Cited UNITED STATES PATENTS 6/1968 Mosby 260-283 P 2/1972 Reimlinger 260--288 OTHER REFERENCES Zimmer et al., Chem. Abstracts, vol. 69, cOl. 52069y. Nair et al., Indian Jour. Chem, vol. 5, pp. 403-8 (1967).
DONALD G. DAUS, Primary Examiner US. Cl. X.R.
260283 S, 283 CU, 287 R, 288 A, 289 R
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3953457A (en) * 1972-07-28 1976-04-27 Eli Lilly And Company Agent for the control of plant-pathogenic organisms
US3974286A (en) * 1975-02-07 1976-08-10 Eli Lilly And Company S-Triazolo [5,1-b]benzothiazoles as fungicidal agents
US3979387A (en) * 1975-06-10 1976-09-07 Eli Lilly And Company 4,5-Dihydrotetrazolo(1,5-A)quinoxalines
US3991063A (en) * 1971-09-09 1976-11-09 Wijbe Thomas Nauta Aminoisoquinolines
US4075341A (en) * 1974-05-24 1978-02-21 Gruppo Lepetit S.P.A. 2-Substituted phenyl-5-triazols [5,1-a] isoquinoline compounds
USRE30456E (en) * 1973-05-25 1980-12-23 Gruppo Lepetit S.P.A. 2-Substituted phenyl-s-triazolo[5,1-a] isoquinoline compounds
US4275066A (en) * 1978-10-30 1981-06-23 Gruppo Lepetit S.P.A. Antireproductive tricyclic ortho-fused nitrogen containing compounds
US20050090521A1 (en) * 2003-09-26 2005-04-28 Rigel Pharmaceuticals, Inc. HCV inhibitors and methods of using them

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991063A (en) * 1971-09-09 1976-11-09 Wijbe Thomas Nauta Aminoisoquinolines
US3953457A (en) * 1972-07-28 1976-04-27 Eli Lilly And Company Agent for the control of plant-pathogenic organisms
USRE30456E (en) * 1973-05-25 1980-12-23 Gruppo Lepetit S.P.A. 2-Substituted phenyl-s-triazolo[5,1-a] isoquinoline compounds
US4075341A (en) * 1974-05-24 1978-02-21 Gruppo Lepetit S.P.A. 2-Substituted phenyl-5-triazols [5,1-a] isoquinoline compounds
US3974286A (en) * 1975-02-07 1976-08-10 Eli Lilly And Company S-Triazolo [5,1-b]benzothiazoles as fungicidal agents
US4075218A (en) * 1975-02-07 1978-02-21 Eli Lilly And Company S-Triazolo[5,1-b]benzothiazoles
US3979387A (en) * 1975-06-10 1976-09-07 Eli Lilly And Company 4,5-Dihydrotetrazolo(1,5-A)quinoxalines
US4275066A (en) * 1978-10-30 1981-06-23 Gruppo Lepetit S.P.A. Antireproductive tricyclic ortho-fused nitrogen containing compounds
US20050090521A1 (en) * 2003-09-26 2005-04-28 Rigel Pharmaceuticals, Inc. HCV inhibitors and methods of using them
US7358259B2 (en) 2003-09-26 2008-04-15 Rigel Pharmaceuticals, Inc. HCV inhibitors and methods of using them

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